By Eleanor Licata

Anew drug is revolutionizing treatment for cystic fibrosis by treating the life-threatening disease at its source, instead of simply addressing the symptoms.

“It’s a huge step to actually direct the drug at the protein to get it to work more effectively,” says Bonnie Ramsey M.D., Res. ’79, UW professor and vice chair for research in the Department of Pediatrics. She’s also the director of the Center for Clinical and Translational Research at Seattle Children’s and the holder of the Bonnie W. Ramsey, M.D. Endowed Chair in Cystic Fibrosis.

A drug called Orkambi holds the key; it corrects the malfunctioning protein that causes cystic fibrosis in about half of the people with the disease. And as lead investigator for the phase III clinical trials of the drug, Ramsey played an instrumental role in the development and approval of Orkambi — bringing the cystic fibrosis community that much closer to finding a cure.

A Day in the Life

Cystic fibrosis patient Nathan Schmidt describes his daily routine — and an argument for more and better treatments for CF.

When I get up in the morning, I inhale several medications, including saline. I also take medication to help me digest fats and proteins, and I do physical therapy — I blow into a device that shakes the air in my lungs and allows me to cough up mucus. Otherwise, it would collect and lead to infections.

Exercise is definitely recommended. I bike, run and rock climb.

Growing up, I had to do 45-minute sessions of physical therapy several times a day to loosen the mucus. Self-care gets harder in college because you’re experiencing independence for the first time. Then, if you have a full-time job, it’s difficult to find the time. You might have to sacrifice things like sleep, friends or even work.

Photo: Clare McLean

The burden of cystic fibrosis

More than 30,000 people in the U.S. and 70,000 worldwide have cystic fibrosis (CF), a rare, life-threatening genetic disease.

The problem lies in a defective protein that normally operates as a salt channel. This defective channel in CF patients creates a salt imbalance, which makes the body’s mucus extra thick and viscous. Over time, mucus build-up in the lungs, pancreas and other organs leads to persistent lung infections and problems with digestion. These bacterial lung infections, called pulmonary exacerbations, require multiple hospitalizations and pose one of the greatest threats to CF patients’ lives.

When the Cystic Fibrosis Foundation Patient Registry began tracking data in 1966, life expectancy for patients was short: limited to early childhood. Today, life expectancy for a CF patient is close to 40 years of age, a major improvement — one made possible by inhaled antibiotics and other therapies. An improvement that will be enhanced, hopes Ramsey, by Orkambi.

Living on borrowed time

After training as a pediatrician at Boston Children’s Hospital, Ramsey came to Seattle Children’s. Studying cystic fibrosis was not in her plans. “I was planning on being a pediatric oncologist. But I took a year off and was asked to cover the CF clinic because they were between physicians. And I just loved the patient population,” she says.

Nate Schmidt was one of Ramsey’s patients. Shortly after birth, he was diagnosed with the most common type of CF. A medical resident called his parents to tell them he probably wouldn’t live past elementary school. “Thankfully, that wasn’t the case,” says Schmidt, now 29 and working for Gilead, a biotech firm in Seattle. “But that was the prognosis at the time.”

It was working with children like Schmidt, living on borrowed time, that inspired Ramsey to change course and develop a clinical research program around cystic fibrosis — and to become a pediatric pulmonologist.

The needle in the haystack

When the gene responsible for cystic fibrosis was discovered in 1989, a wealth of new information on the disease began to pour in. Researchers found more than 1,800 different kinds of mutations in the CF gene with different effects on the CF protein. Some mutations don’t make the CF protein at all. Others make a protein that misfolds, and some mutations make proteins that fold, but are unable to open once they reach the cell surface.

Different forms of the disease would require different approaches, researchers realized. In order to be effective, therapies would need to be directed toward specific genotypes. Much more research would need to be done to create treatments that would work for individual patients, and Ramsey was part of that work.

In 1997, the Cystic Fibrosis Foundation asked Ramsey to put together a clinical trials network. The following year, with funding from the foundation and the National Institutes of Health, Ramsey created the Therapeutic Development Network, which she helped build into the largest CF clinical trials network in the world.

“We started developing a whole new range of therapies and working with companies to get them interested in cystic fibrosis,” Ramsey says.

Around the same time, the Cystic Fibrosis Foundation provided grants to several laboratories to begin high-throughput screening. Using vast chemical libraries, researchers used sophisticated, rapid-performance equipment to look for compounds that could correct the abnormal CF protein. The likelihood of them finding anything? “Worse than finding a needle in a haystack,” Ramsey says.

Nate Schmidt, 29, visits his physician, Moira L. Aitken, M.D., at the UW Medicine Adult Cystic Fibrosis Clinic, one of the first of its kind in the nation. Schmidt was part of the clinical trial for Orkambi.

Photo: Clare McLean

But high-throughput screening found the needle: several potential chemical compounds that could fix the malfunction. Vertex Pharmaceuticals developed them into potentiators, which open the CF protein so it can work as a salt channel, and correctors, which help the CF protein fold and get to the cell surface.

Orkambi is a combination of a potentiator called Kalydeco, which dramatically improves lung function for about 5 percent of patients with CF, and a corrector called lumacaftor. This new drug combination, Orkambi, is designed to treat people with two copies of the F508del mutation — the most common type of cystic fibrosis, affecting around half of the people who suffer from the disease.

Before Orkambi could be approved by the FDA, it had to be proved safe and effective through clinical trials. This was the challenge Ramsey and her team faced: how to translate discoveries made in the lab into safe products for patients.

Crossing the finish line

Working with the Cystic Fibrosis Foundation and Vertex Pharmaceuticals, Ramsey and her team helped design and conduct several phase III double-blind, placebo-controlled clinical trials for Orkambi, involving more than 1,100 people with CF. Participants, age 12 and older, came from multiple countries.

“Long before any promising drugs had been identified, we were thinking, ‘What do we have to do to be ready?’” Ramsey says. “I thought of it like a relay. Our group was the last ‘runner’ in the relay. So you’re waiting for the baton to come, but then you’ve got to go finish the race.”

Designing these clinical trials raised a lot of questions. What would they use to measure a change in salt production? How many patients would they include, and where would they find them? Perhaps most importantly, Ramsey says, “How are we going to know we’re there? That’s what’s really scary. You could have a ‘cure’ in the laboratory, but how are you going to detect it to the point where the FDA will approve it, which is your ultimate goal?”

When Schmidt heard about the trial from the UW Medicine Adult Cystic Fibrosis Clinic at UW Medical Center, he lost no time signing up. The clinic, which was recruiting patients for the trial, was established more than 25 years ago by his physician, Moira Aitken, M.D. Schmidt enrolled in the study, and in October 2013, he participated in an extension study. He’s been taking Orkambi ever since.

“I felt normal. I didn’t notice anything different,” says Schmidt. But, he reasons, that’s probably what the drug is designed to do — keep you level and out of the hospital.

“Most people with CF end up visiting the hospital two to three times a year,” he says. “I haven’t been to the hospital for an exacerbation in years. Fingers crossed it won’t happen any time soon.”

“Now, when I go into the room…I really can provide families with hope.” — Bonnie Ramsey, M.D., Res. ’79

The good news

In July 2015, Orkambi received FDA approval. The results look good. Orkambi improved lung function around 2 to 4 percent — not a huge increase, but a significant one. “But once you get that improvement, [the patient is] stable for 12 months,” says Ramsey. “This is very encouraging.”

Stability, as Schmidt notes, is really important to patients. One of the biggest measures of improvement for people taking Orkambi has been the striking decrease — around 40 to 60 percent — in the frequency of pulmonary infections.

This means fewer hospitalizations for patients, a better quality of life, and possibly a longer life for many people with cystic fibrosis. Although it’s still too early to tell what Orkambi’s full impact will be, it’s a decided victory for everyone who’s worked on the drug.

Ramsey stresses the importance of teamwork in Orkambi’s development and approval: the Cystic Fibrosis Foundation, which has awarded approximately $25 million to UW Medicine since 1988, played a vital role. As did patients, industry and care teams. “I think it’s an example of when a whole lot of people work together for a common cause, you can really make a difference,” she says.

Offering hope

In the meantime, more research awaits.There are still CF patients with gene mutations that aren’t addressed by any treatments on the market.

However, with the release of Kalydeco in 2012 and Orkambi in 2015, more than 50 percent of CF patients have a new reason to hope. And so does Ramsey.

“I can remember sitting down with a family and feeling like I could provide comfort, but not really hope,” Ramsey says. “And now when I go into the room, it’s so different because I really can provide them hope.”

Schmidt is familiar with this feeling of cautious excitement. “Just about everybody with this disease is…watching the development timeline of these products that come up,” he says. “We’re always cheering the team on.”